Article

From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy.

Department of Pathology, University of Minnesota School of Medicine, Duluth, MN, USA.
Parasitology Research (Impact Factor: 2.33). 03/2012; 111(1):1-6. DOI: 10.1007/s00436-012-2886-x
Source: PubMed

ABSTRACT Malarial treatment is widely and readily available today. However, there was a time in the not-so-distant past when malaria was a deadly disease with no known cause or cure. In this article, we trace the origins of an antimalarial therapy from the discovery of the nature of the malarial parasite through the development of chloroquine. We dedicate this article to Johann "Hans" Andersag, the scientist who developed chloroquine, on the 110th anniversary of his birth, 16 February 1902.

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    ABSTRACT: For many years chloroquine was used as a prophylactic agent against malaria, and more recently as a mild immunosuppressive. However, due to lengthy treatment periods, adverse effects have become apparent, which included retinopathy. The structurally related hydroxychloroquine is less toxic, thought to be owing to a lower tissue accumulation in melanin rich areas. This study primarily focused on quantifying melanin binding between chloroquine and hydroxychloroquine at physiological pH to investigate the potential link between binding and reported toxicity. In addition, for the first time this study quantified the actual extent of adsorption of chloroquine and hydroxychloroquine to melanin and examined the desorption profile of both drugs from melanin to demonstrate the affinity between the pigment and the solutes. The results suggest that there is a difference between the adsorption affinities of chloroquine and hydroxychloroquine, potentially explaining the differences in bioaccumulation in retinal tissue. In addition, both solutes displayed a strong physical attraction to the absorbent.
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    ABSTRACT: Summary The redox dye, methylene blue (MB) is proved to have beneficial effects in various models of neurodegenerative diseases. Here we investigated the effects of MB (100nM, 300nM and 1μM) on key bioenergetic parameters and on H2O2 production/elimination in isolated guinea-pig brain mitochondria under normal as well as respiration-impaired conditions. As measured by High Resolution Oxygraph the rate of resting oxygen consumption was increased, but the ADP-stimulated respiration was unaffected by MB with either substrate (glutamate-malate, succinate or alpha-glycerophosphate) used for supporting mitochondrial respiration. In mitochondria treated with inhibitors of complex I or complex III MB moderately but significantly increased the rate of ATP production, restored ΔΨm and increased the rate of Ca(2+)-uptake. The effects of MB are consistent with transferring electrons from upstream components of the electron transport chain to cytochrome c, which is energetically favorable when the flow of electrons in the respiratory chain is compromised. On the other hand, MB significantly increased the production of H2O2 measured by Amplex UltraRed fluorimetry in all conditions; both in resting, ATP-synthesizing and respiration-impaired mitochondria with each substrate combination supporting respiration. Furthermore, it also decreased the elimination of H2O2. Generation of H2O2, without superoxide formation, observed in the presence of MB is interpreted as a result of reduction of molecular oxygen to H2O2 by the reduced MB. The elevated generation and impaired elimination of H2O2 should be considered for the overall oxidative state of mitochondria treated with MB.
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    ABSTRACT: Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQ GREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQ GREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive-or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQ GREEN , which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC 50 s were determined. These data were compared with LynxTag-CQ GREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC 50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y. Copyright: ß 2014 Loh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: As part of the Oxford Tropical Medicine Research Program of Wellcome Trust–Mahidol University, Shoklo Malaria Research Unit (SMRU) is funded by the Wellcome Trust of Great Britain. The authors further thank the National Research Foundation (NRF2009NRF-POC002–102), the National Medical Research Council (NMRC/1310/2011; NMRC/EDG/1038/2011), and the Agency for Science, Technology and Research (A*STAR, Singapore) for their generous support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: KSWT and MJL are founding directors of BioLynx Technologies (Singapore), a private company that specializes in fluorophore-conjugated drug surrogates including LynxTag-CQGREEN. Other authors declare no competing interests. KSWT and MJL own minority shares in BioLynx Technologies (Singapore). LR and BR are PLOS ONE Editorial Board Members. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria. (LMCC) . These authors contributed equally to this work.
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